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WO 2017/201449 Al 23 November 2017 (23.11.2017) W !P O PCT

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WO 2017/201449 Al 23 November 2017 (23.11.2017) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/201449 Al 23 November 2017 (23.11.2017) W !P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, A61K 47/54 (2017.01) A61P 35/00 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, A61K 47/68 (2017.01) HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (21) International Application Number: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PCT/US201 7/0336 11 PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (22) International Filing Date: SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, 19 May 2017 (19.05.2017) TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/339,257 20 May 2016 (20.05.2016) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant (for all designated States except AL, AT, BE, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, KM, ML, MR, NE, SN, TD, TG). NO, PL, P T RO, RS, SE, SI, SK, SM, TR): GENENTECH, [US/US]; 1 DNA Way, South San Francisco, Califor INC. Declarations under Rule 4.17: nia 94080 (US). — as to applicant's entitlement to apply for and be granted a (71) Applicant (for AL, AT, BE, BG, CH, CN, CY, CZ, DE, DK, patent (Rule 4.1 7(H)) EE, ES, FI, FR, GB, GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, — as to the applicant's entitlement to claim the priority of the MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR earlier application (Rule 4.17(Hi)) only): F. HOFFMANN-LA ROCHE AG [CH/CH]; Gren- — of inventorship (Rule 4.1 7(ivf) zacherstrasse 124, 4070 Basel (CH). Published: (72) Inventors: PILLOW, Thomas; c/o Genentech, Inc., 1 — with international search report (Art. 21(3)) DNA Way, South San Francisco, California 94080 (US). — with sequence listing part of description (Rule 5.2(a)) SADOWSKY, Jack; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). STABEN, Leanna; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). STABEN, Steven; c/ o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). WEI, Binqing; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). WERTZ, Ingrid; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). ADHIKARI, Pragya; c/o Genentech, Inc., 1 DNA Way, South San Fran cisco, California 94080 (US). BLAQUIERE, Nicole; c/o Genentech, Inc., 1 DNA Way, South San Francisco, Cali fornia 94080 (US). DRAGOVICH, Peter; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). FAIRBROTHER, Wayne; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). (74) Agent: CRISSEY, Todd, M. et al; c/o Genentech, Inc., 1 DNA Way, Mail Stop 49, South San Francisco, California 94080 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, o l (54) Title: PROTAC ANTIBODY CONJUGATES AND METHODS OF USE (57) Abstract: The subject matter described herein is directed to antibody-PROTAC conjugates (PACs), to pharmaceutical composi- tions containing them, and to their use in treating diseases and conditions where targeted protein degradation is beneficial. PROTAC ANTIBODY CONJUGATES AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. provisional Application No. 62/339,257 filed 20 May 2016, the contents of which application is hereby incorporated by reference in its entirety. REFERENCE TO A SEQUENCE LISTING SUBMITTED AS A TEXT FILE VIA EFS-WEB The official copy of the sequence listing is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file named SEQLIST.TXT, created on May 20, 2016, and having a size of 77 kilobytes and is filed concurrently with the specification. The sequence listing contained in this ASCII formatted document is part of the specification and is herein incorporated by reference in its entirety. SEQ ID NOs. 1-6 are intentionally omitted. FIELD OF THE INVENTION The subject matter described herein relates generally to antibody-(proteolysis- targeting chimera) (PROTAC) conjugate molecules that are useful for facilitating intracellular degradation of target proteins. BACKGROUND Cell maintenance and normal function requires controlled degradation of cellular proteins. For example, degradation of regulatory proteins triggers events in the cell cycle, such as DNA replication, chromosome segregation, etc. Accordingly, such degradation of proteins has implications for the cell's proliferation, differentiation, and death. While inhibitors of proteins can block or reduce protein activity in a cell, protein degradation in a cell can also reduce activity or remove altogether the target protein. Utilizing a cell's protein degradation pathway can, therefore, provide a means for reducing or removing protein activity. One of the cell's major degradation pathways is known as the ubiquitin-proteasome system. In this system, a protein is marked for degradation by the proteasome by ubiquitinating the protein. The ubiqitinization of the protein is accomplished by an E3 ubiquitin ligase that binds to a protein and adds ubiquitin molecules to the protein. The E3 ubiquitin ligase is part of a pathway that includes E l and E2 ubiquitin ligases, which make ubiquitin available to the E3 ubiquitin ligase to add to the protein. To harness this degradation pathway, PROTACs have been developed. PROTACs bring together an E3 ubiquitin ligase with a protein that is to be targeted for degradation. To facilitate a protein for degradation by the proteasome, the PROTAC is comprised of a group that binds to an E3 ubiquitin ligase and a group that binds to the protein one wishes to degrade. These groups are typically connected with a linker. This molecular construct can bring the E3 ubiquitin ligase in proximity with the protein so that it is ubiquitinated and marked for degradation. There is an ongoing need in the art for enhanced and targeted delivery of PROTACs to cells that contain the protein target. Targeted delivery using antibody-PROTAC conjugates can enhance delivery of PROTACs to particular cells using the specificity of an antibody and can also enhance the pharmacokinetics of delivery of PROTACs to cells relative to other modes of administration of PROTACs, such as infusion. SUMMARY OF THE INVENTION In one aspect, the subject matter described herein is directed to a PROTAC-antibody conjugate (PAC) having the formula: Ab—(LI— D)p, wherein, D is a PROTAC having the structure E3LB—L —PB; wherein, E3LB is an E3 ligase binding group covalently bound to L2; L2 is a linker covalently bound to E3LB and PB; PB is a protein binding group covalently bound to L2; Ab is an antibody covalently bound to LI; LI is a linker, covalently bound to Ab and to D; and p has a value from about 1 to about 8. Another aspect of the subject matter described herein is a pharmaceutical composition comprising a PAC, and one or more pharmaceutically acceptable excipients. Another aspect of the subject matter described herein is the use of a PAC in methods of treating conditions and diseases by administering to a subject a pharmaceutical composition comprising a PAC. Another aspect of the subject matter described herein is a method of making a PAC. Another aspect of the subject matter described herein is an article of manufacture comprising a pharmaceutical composition comprising a PAC, a container, and a package insert or label indicating that the pharmaceutical composition can be used to treat a disease or condition. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the detection of ER-a by Western blot for PROTAC (without Ab), compound PI, and PROTAC-antibody conjugates (PACs) PAC1, and PAC2. Figure 2 depicts the quantitation of ERa as determined by fluorescence intensity for Endox-XIAP PACs treated for 3 days in an engineered HER2-MCF7 line. Media: 10% CS- FBS in phenol red free-RPMI. DETAILED DESCRIPTION Disclosed herein, are antibody-proteolysis targeting chimera conjugates, referred to herein as PROTAC-Antibody conjugates (PACs), that are useful in targeted protein degradation, and the treatment of related diseases and disorders. The subject matter described herein utilizes antibody targeting to direct a PROTAC to a target cell or tissue. As described herein, connecting an antibody to a PROTAC to form a PAC has been shown to deliver the PROTAC to a target cell or tissue. As shown herein, e.g. in Examples 1 and 2, a cell that expresses an antigen can be targeted by an antigen specific PAC, whereby the PROTAC portion of the PAC is delivered intracellularly to the target cell.
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